Antibody-based microbicides are an attractive strategy for preventing gonorrhea in women based on the Isafety, efficacy and the long-standing clinical use of antibodies (Abs) to prevent infection and, or disease. We hypothesize Abs that interfere with the ability of Neisseria gonorrhoeae (GC) to evade host innate defenses will be more effective than those that prevent infection through antibody-mediated clearance mechanisms alone. To facilitate the development of prophylactic agents against GC, we developed a female mouse model of GC lower genital tract infection. Here we propose to test three GC surface molecules (MtrE, sialyl-transferase (Lst), and Opacity (Opa) proteins) that have a detectable impact on GC survival in mice as potential targets of antibody-based microbicides. We will also test porin-specific Abs based on strong in vitro evidence that porin protects against complement-mediated defenses. Specifically, we will i.) assess the effectiveness of Abs to surface-exposed regions of MtrE, the outer membrane channel of the MtrCDE and FarAB, MtrE efflux systems, in decreasing GC resistance to antimicrobial agents in vitro and in preventing experimental infection in mice, ii.) Define the potential of Abs specific for GC porin loops involved in down-regulation of complement activation to decrease serum resistance in vitro and to prevent experimental murine infection iii.) determine the effectiveness of Abs against alpha-2,3 sialyltransferase (LsO in protecting GC from CMP-NANA-dependent serum resistance in vitro and in reducing GC infectivity in mice, and iv.) assess the functional activities of Abs against the first semivariable and fourth conserved surface exposed loops of GC Opa proteins and the capacity of these Abs to prevent GC infection in mice. The protective potential of Abs specific for the target in each aim will be assessed by measuring agglutination, bactericidal, and opsono-phagocytic activity; antibody-mediated inhibition of target molecule function will also be tested. Abs with activity in one or more of these functional assays will be tested for the capacity to passively prevent lexperimental murine GC infection. These studies will allow us to define correlates of protection, which may lead to the development of effective monoclonal antibody-based microbicides and mucosal vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI031496-18
Application #
7668432
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2008-09-01
Budget End
2009-07-31
Support Year
18
Fiscal Year
2008
Total Cost
$332,966
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Zhu, Weiyan; Tomberg, Joshua; Knilans, Kayla J et al. (2018) Properly folded and functional PorB from Neisseria gonorrhoeae inhibits dendritic cell stimulation of CD4+ T cell proliferation. J Biol Chem 293:11218-11229
Des Marais, Andrea C; Zhao, Yuqian; Hobbs, Marcia M et al. (2018) Home Self-Collection by Mail to Test for Human Papillomavirus and Sexually Transmitted Infections. Obstet Gynecol 132:1412-1420
Scheidell, Joy D; Beau De Rochars, Valery Madsen; Séraphin, Marie Nancy et al. (2018) Socioeconomic Vulnerability and Sexually Transmitted Infection Among Pregnant Haitian Women. Sex Transm Dis 45:626-631
Knilans, Kayla J; Hackett, Kathleen T; Anderson, James E et al. (2017) Neisseria gonorrhoeae Lytic Transglycosylases LtgA and LtgD Reduce Host Innate Immune Signaling through TLR2 and NOD2. ACS Infect Dis 3:624-633
Gallo, Maria F; Legardy-Williams, Jennifer; Steiner, Markus J et al. (2017) Sexual Relationship Power and Semen Exposure Among Female Patients at a Sexually Transmitted Infection Clinic in Kingston, Jamaica. Arch Sex Behav 46:2157-2164
Woolf-King, Sarah E; Muyindike, Winnie; Hobbs, Marcia M et al. (2017) Vaginal Prostate Specific Antigen (PSA) Is a Useful Biomarker of Semen Exposure Among HIV-Infected Ugandan Women. AIDS Behav 21:2141-2146
Samo, Melissa; Choudhary, Neelima R; Riebe, Kristina J et al. (2016) Immunization with the Haemophilus ducreyi trimeric autotransporter adhesin DsrA with alum, CpG or imiquimod generates a persistent humoral immune response that recognizes the bacterial surface. Vaccine 34:1193-200
Kandler, Justin L; Acevedo, Rosuany Vélez; Dickinson, Mary Kathryne et al. (2016) The genes that encode the gonococcal transferrin binding proteins, TbpB and TbpA, are differentially regulated by MisR under iron-replete and iron-depleted conditions. Mol Microbiol 102:137-51
Kandler, Justin L; Holley, Concerta L; Reimche, Jennifer L et al. (2016) The MisR Response Regulator Is Necessary for Intrinsic Cationic Antimicrobial Peptide and Aminoglycoside Resistance in Neisseria gonorrhoeae. Antimicrob Agents Chemother 60:4690-700
Kissinger, Patricia J; White, Scott; Manhart, Lisa E et al. (2016) Azithromycin Treatment Failure for Chlamydia trachomatis Among Heterosexual Men With Nongonococcal Urethritis. Sex Transm Dis 43:599-602

Showing the most recent 10 out of 131 publications